Causal relationships between circulating inflammatory factors and IgA vasculitis: a bidirectional Mendelian randomization study

Background IgA vasculitis (IgAV) is an immune-associated vasculitis, yet its exact etiology remains unclear. Here, we explore the interaction between IgAV and inflammatory factors using bidirectional Mendelian randomization (MR). Methods We conducted a bidirectional summary-level MR analysis to delineate the causality of C-reactive protein (CRP), procalcitonin (PCT), and 41 circulating inflammatory regulators with IgAV. Data on genetic variants related to inflammation were obtained from three genome-wide association studies (GWASs) on CRP, PCT, and human cytokines, whereas data on IgAV was from large meta-analyses of GWAS among 216 569 FinnGen Biobank participants. The primary MR analysis was performed using the inverse-variance weighted (IVW) approach, and the sensitivity analyses were carried out using MR-Egger, weighted median, weighted mode, and MR-pleiotropy residual sum and outlier. Results This study revealed the association of CRP higher levels with increased risk of IgAV through IVW method (Estimate odds ratio [OR] = 1.41, 95% confidence interval [CI]: 1.01-1.98, P = 0.04), MR-Egger (OR = 1.87, CI: 1.15-3.02, P = 0.01), weighted median (OR = 2.00, CI: 1.21-3.30, P = 0.01) and weighted mode (OR = 1.74, CI: 1.13-2.68, P = 0.02). Furthermore, elevated IL-8 was strongly implicated with a higher risk of IgAV (IVW OR = 1.42, CI: 1.05-1.92; P = 0.02). Conversely, genetically predicted IgAV was associated with decreased levels of TNF-β (IVW estimate β = -0.093, CI: -0.178 - -0.007; P = 0.033). Additionally, no such significant statistical differences for other inflammatory factors were found. Conclusion Our current study using bidirectional MR analysis provides compelling evidence for a causal effect of CRP, PCT, and circulating inflammatory regulators on IgAV. These findings contribute to a better understanding of the pathogenesis of IgAV and emphasize the potential of targeting inflammatory factors for therapeutic interventions.


Table of contents
Table S1.Details of C-reactive protein predicting SNPs with IgA vasculitis.
Table S2.Details of IgA vasculitis predicting SNPs with C-reactive protein.
Table S3.Bidirectional causal association between IgA vasculitis and C-reactive protein using Mendelian randomization.
Table S4.Details of C-reactive protein predicting SNPs with IgA vasculitis in validation cohort.
Table S5.Details of procalcitonin predicting SNPs with IgA vasculitis.
Table S6.Details of IgA vasculitis predicting SNPs with procalcitonin.
Table S7.Bidirectional causal association between IgA vasculitis and procalcitonin using Mendelian randomization.
Table S8.Details of circulating inflammatory regulators predicting SNPs with IgA vasculitis (with genome-wide significant SNPs).
Table S10.Association of circulating inflammatory regulators with IgA vasculitis using Mendelian randomization (with genome-wide significant SNPs).
F-statistic >10 suggests sufficient strength to ensure the validity of the instrumental variable.
Beta for CRP represents change in percent per 1 copy of effect allele.Log(OR) for IgA vasculitis represents log(OR) change in IgA vasculitis risk per 1 copy of effect allele.
Table S3.Bidirectional causal association between IgA vasculitis and C-reactive protein using Mendelian randomization.Abbreviations: log(OR), log odds ratio.
F-statistic >10 suggests sufficient strength to ensure the validity of the instrumental variable.
Beta for CRP represents change in percent per 1copy of effect allele Log(OR) for IgA vasculitis represents log(OR) change in IgA vasculitis risk per 1 copy of effect allele.Abbreviations: log(OR), log odds ratio.
F-statistic >10 suggests sufficient strength to ensure the validity of the instrumental variable.
Beta for procalcitonin represents change in percent per 1 copy of effect allele.
Log(OR) for IgA vasculitis represents log(OR) change in IgA vasculitis risk per 1 copy of effect allele.Abbreviations: log(OR), log odds ratio.
F-statistic >10 suggests sufficient strength to ensure the validity of the instrumental variable.
Beta for procalcitonin represents change in percent per 1 copy of effect allele.
Log(OR) for IgA vasculitis represents log(OR) change in IgA vasculitis risk per 1 copy of effect allele.OR and 95% CI represent change in odds ratio of IgA vasculitis per 1 percent increase in procalcitonin level.
Beta and 95% CI represent change in percent of procalcitonin per log odds increase in IgA vasculitis.F-statistic >10 suggests sufficient strength to ensure the validity of the instrumental variable.
Beta for circulating inflammatory regulators represents change in standard deviation per 1 copy of effect allele.
Log(OR) for IgA vasculitis represents log(OR) change in IgA vasculitis risk per 1 copy of effect allele.
Table S9 displayed in Table S9.xlsx.OR and 95% CI represent change in odds ratio of IgA vasculitis per 1 SD increase in circulating inflammatory regulators level.
After correcting for multiple comparison, P-value < 0.05 was considered as significant.
Table S11.Association of circulating inflammatory regulators with IgA vasculitis using Mendelian randomization (with SNPs reaching P< 1 x 10-5).OR and 95% CI represent change in odds ratio of IgA vasculitis per 1 SD increase in circulating inflammatory regulators level.
After correcting for multiple comparison, P-value < 0.05 was considered as significant.
Table S13.Association of IgA vasculitis with circulating inflammatory regulators using Mendelian randomization (with SNPs reaching P<1 x 10-5).Beta and 95% CI represent change in SD of circulating inflammatory regulators per log odds increase in IgA vasculitis.
After correcting for multiple comparison, P-value< 0.05 was considered as significant.

Figure S1 .
Figure S1.The causal effects and sensitivity analysis of CRP on IgAV in validation cohort.A) The causal effect of CRP on IgAV.B) MR leave-one out sensitivity analysis for CRP on IgAV.C) MR effect size for CRP on IgAV.D) Causal estimate for different MR tests.

Table S1 .
Details of C-reactive protein predicting SNPs with IgA vasculitis.

Table S2 .
Details of IgA vasculitis predicting SNPs with C-reactive protein.

Table S4 .
Details of C-reactive protein predicting SNPs with IgA vasculitis in validation cohort.

Table S5 .
Details of procalcitonin predicting SNPs with IgA vasculitis.

Table S6 .
Details of IgA vasculitis predicting SNPs with procalcitonin.

Table S8 .
Details of circulating inflammatory regulators predicting SNPs with IgA vasculitis (with genome-wide significant SNPs).

Table S10 .
Association of circulating inflammatory regulators with IgA vasculitis using Mendelian randomization (with genome-wide significant SNPs).